Halogenated compounds for synthesizing steroids



United States Patent HALOGENATED COMPOUNDS FOR SYNTHESIZIN G STEROIDS Martin W. Farrar, Webster Groves, vHarold Ralfelson, St. Louis, and William S. Knowles,'Kirkwo'od, Mo., assignors to Monsanto Chemical Company, St. L'ouis, Mo., a corporation of Delaware N0 Drawing. Original application July 23, 1953, Serial No. 369,944, now Patent No. 2,759,929, dated August 21, 1956. Divided and this application June 21, 1956, U

Serial No. 592,729

10 Claims. (Cl. 260397.45)

This invention relates to methods and novel compounds of the cyelopentanodimethylpolyhydrophenanthrene series having a 3-keto group and a double bond in the 4,5 position, which compounds are intermediates in pro ceeding from a 17-formyl-cyclopent-16-eno-10,13-dimeth- QHzOR Patented Nov. 4,1958

ing from a 17-formyl-cyelopent-16-eno-10,13-dimethyl- A -decahydrophenanthren-3-one to a 17-(acyloxyacetyl) 17 hydroxycyclopentano 10,13 dimethyl- A dodecahydrophenanthren 3,11 dione essentially comprises (1) epoxidizing a 17-formyl-cyclopent-16-eno- 10,13 dimethyl A4301) decahydrophenanthren 3- one with an oxyg'n furnishing agent, (2) converting the formylgroup of, the 16,17-oxido compound so formed to a carboxyl group, (3) reacting the carboxylic acid so obtained with an acyl halide forming agent, (4) reacting the resultant acid halide with diazomethane, (5) reacting the diazo-ketone so formed with a carboxylic acid to form a 17-(acyloxyacetyl)-16,17-oxido-cyclopentano-l0, 13-dimethyl-A 9( 1) decahydrophenanthren-3-one, (6) reacting said latter compound with, a hydrogen halide,j (7) reacting the 16 halo 17 hydroxy 17 (acyloxyacetyl) cyclopentano 10,13 dimethyl A deca-. hydrophenanthren-3-one so formed with a hypohalous acid, (8) oxidizing the 9,16-dihalo-11,17-dihydroxy-17- (acyloxyacetyl) cyclopentano 10,13 dimethyl- A dodecahydrophenanthren-3-one with a complex of chro mium oxide and a tertiary amine, (9) de-halogenating the 9,16-dihalo-I'Z-hydroxy-17-(acyloxyacetyl)-cyc1opentano- 10,13 dimethyl A dodecahydrophenanthrem 3,11-dione so as to produce a 17-acyloxyacety1) -1'l-hydroxy-cyclopentano-10,13 dimethyl A dodecahydrophenanthren-B,1l-dione. The aforesaid sequence of steps is outlined schematically as followsr This in vention will be described in detail with respect to its preferred embodiment but it is to be understood that such is not limitative of this invention.

The first step" in the process of this invention is the epoxidation' -of a 17-formyl-cyclopent-16-eno-10,13-dimethyl A decahydrophenanthren 3 one to a 16,17 -oxido' --17 formyl cyclopentano 10,13 di-' methyl -A*' decahydrophenanthren 3 one (Compound -11) employing an oxygen furnishing agent such :as the organic per-acids or'hydrogen peroxide in an amount corresponding 'toapproximately one chemical equivalent. The epoxidation-isjordinarily carried out by mixing the oxidant and the lWformyl-cyclopent-l6eeno-lO,l3-dimethyl-A -decahydrophenanthren-3-one together in an organic medium which is non-reactive under the reaction conditions. Suitable media include chloroform, carbon tetrachloride, diethyl ether, glacial acetic acid, methanol, ethanol, isopropanol, and the like. The temperature employed in the epoxidation may vary widely but ordinarily will be in the range of from about C. to about 50 C. A convenient reaction medium when the oxidant is hydrogen peroxide is a low molecular weight alcohol.

As illustrative .of the first step of the process of this invention is the following: I

Exam p l e I To a suitable reaction vessel containing 50 parts by weight (substantially 0.169 mol) of dl-3-keto-l7-formyl- A -androstatriene (M. P. l78l78.5 C.) dissolved in 4200 parts by weight of methanol maintained. at about 5 C. is added approximately 170 parts by weight of sodium carbonate as a 5% aqueous solution followed by a methanol-hydrogen peroxide containing approximately 5.7 parts by weight of hydrogen peroxide. The mix so-obtained is stirred for about 16 hours at about 0 C. Thereupon substantially 'alljof themethanol is removed by vacuum distillation and the residue is then taken up with chloroform. The chloroform solution is then washed. with water and dried over anhydrous magnesium sulfate. Upon evaporation of the chloroform there is obtained a white soiid're'sidue, which upon triturating with diethyl ether yields white crystallinerll-B- keto-16,17-oxido-17-formyl-A -androstadiene.

Similarly theindividual optically active isomers such as the natural modification of 3-keto-16,l7-oxido-17- formyl-A -androstadiene are obtained beginning with the appropriate optically active isomer of 3-keto-17- formykM androstatriene. The natural modificati'on of 3''keto-16,17-oxido-17-formy1-A -androstadi ene isobtained'employing the procedure of Example I but replacing dl-3-keto-17-f0rmyl-A -androstatriene with the dextro-rota'toryiorm of 3-keto-l'7-formyl- At' -androstatriene (melting'point l'60.5-161.5 CL) The next step in the process of this invention is the conversion of the forrnyl group, i. e. the substituent in the '17'-positio'n, to a carbo'xy group (Compound III of olid residue which upon triturating with diethyl ether.

the schematic diagram). This isreadily brought about employing a mild oxidizing agent such as silver oxide, sodium chromate in acetic acid, and the like. As. illus' trative of the preparation of a -3-keto-l6,17-oxido-l7- carboxy-A -androstadiene is the following:

Example II To an intimate mixture containing approximately 200 parts by weight of dioxane, approximately 192 parts by weight of 2.74 N sodiumhydroxide, and approximately 44.6 parts by weight of silver nitrate is slowly added approximately 40 parts by weight of dl-3-keto-16,17-oxido- 17-formyl-A -androstadiene. Upon completion of the addition of the 16,17-oxido compound approximately 200 parts by weight of water and approximately 200 parts by weight of dioxane is added with constant agitation. Thereafter the mix is agitated for about one hour and is then filtered. The collected residue is washed with water and the washings combined with the original filtrate. The aqueous layer is acidified and then extracted with chloroform. The chloroform extracts are combined, dried and subjected to vacuum distillation. Upon evaporation of the chloroform there is obtained a yields 35 parts by Weight of crystalline dl-3-keto-16,-17- oxide-17-carboxy-A -androstadiene.

. Similiarly the individual optically active isomers such as the natural modification of 3-keto-16,l7-oxido-17-carboxy-A -androstadiene are obtained beginning with the appropriate optically active isomer of 3-keto-16,l7- oxido-l7-formyl-A -androstadiene.

The next step in the process 'of this invention the carboxylic acid- (Compound III) is converted to its acid halide (Compound IV) employing an acyl halide forming agent such as oxalyl chloride and the like. As illustrative of the preparation of the acid halide (Compound IV) is the following:

Example III To a solution containing approximately 50 parts by weight of 'dl-3-keto-16,l7-oxidoJ7-carboxy A androstadiene in approximately 4000 parts by weight of anhydrous methanol is added suflicient sodium methylate to neutralize the epoxy acid. The methanol is removed by vacuum distillation and to the residue isadded and intimately mixed about 450 parts by weight of benzene and about 2.5 parts by weight of pyridine followed by about 250 parts by weight of oxalyl chloride while maintaining the temperature-at about C. The mix so obtained is allowed'to stand for about 30 minutes, whereupon the mix-is subjected to vacuum distillation while maintaining the temperature at about C. The residue is then taken up with about 500 parts by weight of benzene and again subjected to vacuum distillation at about 15 C. The residue istaken up with about 250 parts by weight of benzene and filtered. Upon subjecting the filtrate to vacuum distillation there is obtained the solid acid chloride of dl-3-keto-16,l7-oxido-l7-carboxy-A -androstadiene.

Similarly the individual optically active isomers such as the acid chloride of the natural modification of 3-keto-' l6,l7-oxido-l7-carboxy-A -androstadiene are obtained from the appropriate optically active isomer.

The next step in the process of this invention is the preparation of the diazoketone (Compound V) by reacting diazomethane with an acid halide of a 16,17-oxido-17- carboxy cyclopentano 10,13 dimethyl A decahydrophenanthren-El-one. Ordinarily an excess of two chemical equivalents of diazomethane-is employed in converting the acid halide (Compound IV) to the diazoketone (Compound V) and in general the process is carried out in an inert organic solvent such as diethyl ether, benzene, dioxane, toluene, etc., at a temperature in the range of 20 to 40 C. As illustrative of the preparation of the diazoketone is the following:

Example IV To a suitable reaction vessel containing an ether solution containing 100 parts by weight of diazomethane is added approximately 50 parts by weight of the acid chloride of dl-3-keto-16,17-oxido-17-carboxy-A -an drostadiene dissolved in 500 parts by weight of benzene while maintaining the temperature at about 0 C. The mixture so obtained is then agitated for about one hour at about 0 C. The mix is then subjected to vacuum distillation to remove the solvents whereuponthere is obtained yellow crystalline a l-3,20-diketo-'16,17-oxido-21- Similarly the individual optically active isomers such as the natural modification 0f 3,20-diketo-16,l7-oxido-21- diam-A -pregnadiene are obtained beginning with the acid halide of the appropriate optically active isomer of S-keto-16,17-oxido-17-carboxy-A -androstadiene.

.-The. nextrstep in the process of this invention is the formation of the l7-(acyloxyacetyl)-l6,l7-oxido-cyclopentano 10,13 dimethyl A4301 decahydrophenanthren-3-one (Compound VI) from the diazoketone (Compound V) by heating the latter in the presence of a monocarboxylic' acid such as acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, lauric acid, stearic acid, phenylacetic acid, fi-phenylpropionic acid, benzoic acid, toluic acid, etc., in the presence where desirable of an inert organic solvent such as benzene, toluene, xylene, dioxane, etc. It is preferred that the carboxylic acid be a fatty acid and preferably one containing from 2 to 4 carbon atoms. As'illustrative of this step is the followmg:

Example V To a suitable reaction vessel containing approximately 5000 parts by weight of acetic acid is added approximately 50 parts by weight of dl-3,20-diketo-l6,17-oxido-2l-diazo-d -pregnadiene and the'mix so obtained heated at about -95 C. for about 30 minutes The resulta htf mix'is then subjected to vacuum distillation and the resi due so obtained taken up with chloroform. The chloroform solution is then washed with, aqueous sodium bicarbonate, then with water and'finally dried. Upon removal of the solvent'there is obtained solid dl-3,20. diketo- 16, 17 oxido-2 1-acetyloxya -pregnadiene in the form of white crystals.

Similarly the individual optically active'isomers such as the natural modification of 3,20-diketo-16,17oxido 21- acetyloxy-A i pregnadienej are obtained from the appropriatdopticallyactive isomer of 3,20-diketo-1'6,l7:-

. HBr or HI which results in the formation of a halohydrin (Compound VII), namely 16-halo-17-hydroxy-l7- (acyloxyacetyl)-cyclopentano-10,13-dimethyl-A -decahydrophenanthren-3-one. This reaction is preferably carried out in an ,inert organic-solvent containing dis solved therein the hydrogenhalide reactantand at a temperature 'inthe range of about 20 C. to about 40 C. As illustrative of this step is the following:

' Example VI Z Approximately 40 parts by weight of dl-3,20-diketo-16,

admixed obtained extracted with several small portionsof chloro- I form. The chloroform extracts are combined, washed with water and dried over anhydrous magnesium sulfate. Upon subjecting, the so dried solution to vacuum, distillation in order to remove the chloroform there is obtained white crystalline dl-3,ZO-diketo-IGB-bromo-lfh-hydroxy- 21-acetyloxyA D-pregnadiene.

In a similar fashion but employing hydrogen chloride instead of hydrogen bromide white crystalline dl-3,20-'

diketo-l613-chloro-l7a-hydroxy-2l-acetyloxy-Ai -pregnadiene is obtained from dl-3,20-diketo-l6,17-oxido-2lacetyloxy-A -pregnadiene.

Similarly the individual optically active isomers such as the natural modification of 3,20-diketo-16 3-bromo-l7ahydroxy-2l-acetyloxy-A -pregnadiene are obtained from the appropriate optically active isomer of 3,209,

diketo-16,17-oxido-21-acetyloxy-A -pregnadiene.

The next step in the process of this invention is the reacting of the 16-halo-17-hydroxy compound (Compound VII) with a hypohalous acid to form the 9,16-dihal6-1l,

17 dihydroxy-17-(acyloxyacetyl) -cyclope'ntano-l0,13-di-' methyl A dodecahydrophenanthren-3-one (Compound VIII). The addition reaction is brought about by mixing a'solution of a hypohalous acid, preferably hypobromous acid, with a solution of a 16-halo-l7-hydroxy-l7-(acyloxyacetyl) cyclopentano10,13dimethyl-A -decahydro-. phenanthren-3-one at a temperature in the range of about 0 to 30 C. The 9-halo and ll-hydroxy substituents so introduced bear a trans relationship to one another, that is one occupies the plane above ring C while the other occupies the plane below ring C, however, it is to be understood that the element of this invention is .not

limited to any assumption as to chemical structure but pertains broadly to the 9-halo-l1-hydroxy addition'prodnet of a hypohalous acid and a l6-halo-l7-hydroxy-17- (acyloxyacetyl)-cyclopentano-l0,l3-dimethyl-A -decahydrophenanthren-Z-on'e (Compound VII). Various solvents which are inert, under conditions of theaddition. rcactionmay be; uscdin. the, preparation of. the. 9-halollhydroxy addition. product (Compound VIII), for. example. acetone, methylethyLketone, methyl acetate, ethyl acetate, tert. butanol, etc.

In-this step. of the processof invention it. is preferredthatthehypohalous acid employedbev hypobromous acid and such can be prepared in scyeraltways, for example. by mercuric oxide with. bromide. and

water. and filtering oil the mercuric bromide thus formed,

orv by mixing;N -bromoacetamide;with.water and tertiary butanol or, preferably, by mixing asolution, of N-bromosuccinimide in a suitable inert organic solvent, e. g. acetone, tertiary butanol, with water and a small amount of sulfuric acid. Where desired the. hypobromous acidsolution can be .prepared first and then mixed with 16-halo-17-hydroxy-17- (acyloxyacetyl)-cyclopentano-10,13-dimethyl-A -decahydrophenanthren-3-one (Compound VII) or, preferably, the hypobromous acidis prepared'in the presence of the reactant (i..e. CompoundVII) so that the elements of'hypobromous acid add to the 2-11 double bond as soon asthey are formed; As illustrative of this step of the process of thisinyention'employing hypobromousacid is the following:

Example VII To an agitating solution containing substantially 63 parts by weightof til-3,20rdiketO-16fl-b1'0mOr17ot-hYd1'OXY- 21-acetyloxy-A '9 -pregnadiene, substantially 2800 parts by weight of acetone and substantially 1200 parts by weightof water is added at about 05 C. approximately 50 parts by weight of 1 Nsulfuric acid. To the socooled and, acidifiedsolution is slowly added a solution containing substantially 35 parts. byv weight of. N-bromosuccinimide. in approximately 360 parts by weight of acetone. Upon completion of theN-bromo-succinimide addition the mix is agitated for about 5 hours at about 0-5- C., the bromo-hydrin crystallizes from. the solution during the agitation. At theendof the agitation period aqueous sodium sulfite is addedto destroy the excess N-bromo-succinimide. and then the mix is neutralized.

with sodium bicarbonate. The mix is filteredand the residue-washed first with water, then with acetone and dried. The White. crystalline product so obtained is dl-3,20-diketo- 9u,17;8-- dibromo 115,170: diliydroxy 21-acetyloxy-A Similarly the individual .optically active isomers of 3,20-'

dike to 9,w, 16 8.- dihalo- 1 1 ,B,17u-dihydroxy -21-acetyloxy At-pregnene, .e. g. the, natural modification of 3,20 diketo- 9m,16fl .--dibrorno.,- 11 6,1700: dihydroxy 21-acetyloxy-A ptfegri erne; are; obtained. from the: appropriate, optically active 3,20-diketo-16,8-halor'17a-hydroxy 21 acetyloxy A -pregnadiene.

The next step in the-process of this invention is the oxidation of the l l-hydroxy substituent of Compound ofithe foregoing schematic diagram to produce:- the 16 --hal'o--1'7--hydroxy -17 (acylox-yacetyl) cy-'= clopentano-9=--halo=- -1 0,13 dimethyl A dodiacahy drophenanthrengl li-dione (CompoundDO' where 5c is; a halogen atom such as bromine, chlorine and. iodine and where R is. an acyl radical derived froma hydrocarbon monocarboxy lic acid. This oxidationstep is. brought about in; an. anhydrous system by mixing a complex ofchromium oxide and a tertiary amine,such. as pyridine orthe various picolines; etc., with the 9- halo-1 1-hydroxy compound (Compound VIII). As llllJS-r;

trative' of this step of the process of this invention is the following:

Example. VIII To an agitated complex of" chromium trioxide and pyridine preparedin the cold'by admixing 50 parts by weight of chromium trioxide with" 500 parts by droxy-2l-acetyloxy-A -pregnene in approximately 800 parts by weight of pyridine while maintaining the temperatureat about 10 C. The mixture so obtained is permitted to stand at room hours with occasional agitation. filtered and theresidue washed with pyridine.

form; The extracts are combined and cooled to about 0 C. The cooledsolutionis then washedwith dilute hydrochloric acid and thenwith water. The organic layer is recovered, dried, and evaporated to dryness.-. The residue is white crystalline dl 3,11,20 triketo 9a=,16;8'- dibromo 17a hydroxy 21 acetyloxy A pregnene.

Replacing-di- 3,20 diketo' :,165 dibromo 11p,

17 u-dihydroxy-21 acetyloxy=A -pregnene' in Example VIH with an equal weight ofdl 3,20-diketo-9a,16 3-dichloro' 11 8,17a-dihydroxy-21-acetyloxyA -pregnene and subjecting same to the series of steps set forth in Example VIII-dl 3,11,20 triketo 9a,16,3 dichloro 17a --hydroxy-2l-acetyloxy-A -pregnene is obtained.

In a similar fashion the individual optically active isomers of 3,11,20 triketo-9ot,16B-dihalo-17a-hydroxy-21-- acetyloxy A -pregnene, e. g. the natural modification of 3,11g20 triketo 911.1613 dibromo 17a hydroxy- 21-- acetyloxy-A -pregnene is obtained from the appropri ate optically active 3,20-diketo-9ot,16B-dihalo-l1,8,17a-

dihydroxy-Zl-acetyloxy-A -pregnene.

The nextstepv in the process of this invention isthe removal of the 9-halogen and 16-halogen substituents* on the 16-halo-17-hydroxy-17-(acyloxyacetyl) -cyclopentano 9 halo 10,13 dimethyl-A -dodecahydrophenanthren-3 ,1 l-dione. in-the-9-positionis removed first to provide a 16-halo-.- l7 -hydroxy 17 (acyloxyacetyl) cyclopentano 10,

weight. of'pyridine is. added, substantially 50 parts by weight of dl 3,20 diketo 9,16 dibromo 115,170: dihy-- temperature for about 16- The mixture is then Thepyridine'wash and 'the original-filtrate are combined and the solution so formed is poured intofive times its weightofwater' and the composite extracted with chloro- Y i In this step the halogen substitucnt.

Example 1X To a suitable reaction vessel containing 20 parts by weight of Raney nickel, approximately 200 parts by weight of acetone and about 20 parts by weight of water is added approximately 3.5 parts by weight of dl 3,11,20 triketo 90:,165 -,dibromo -17oz hydroxy- 2l-acetyloxy-A -pregnene'and. the mixture so obtained refluxed in an atmosphere of nitrogen for about-4 hours. The reaction mix is then filtered and the residue washed with warm acetone. The washings and original filtrate are combined and subjected to vacuum distillation. The residue is then taken up with chloroform and the. solution so formed washed with water and dried. The dried solution is then subjected tovacuum distillation whereupon there is obtained white crystalline dl-3,1l,20 -triketol7a-hydroxy-2l-acetyloxy-M-pregnene (M. P. 240- 243" C.) which compound is identical with the acetate of racemic (dl) cortisone.

Similarly the individual optically active. isomers such as the natural modification (dextro-rotary form) of 3,11,20 triketo 17oz hydroxy 21 acetyloxy A pregnene are obtained beginning with the appropriate optically active isomers of 3,11,20-triketo-9a,16B-dibromo-l7a-hydroxy-2l-acetyloxy-A -pregnene. The 21- acyl derivative of the natural modification of 3,11,20-triketo-l7a,2l-dihydroxy-A -pregnene according to infrared spectrum, melting point and optical rotation is identical with the corresponding'acyl derivative of natural cortisone. Thusly, it is to be understood that the optically active isomers referred to hereinbefore as the natural m'odification are" those which through the course of reactions asafore schematically outlined starting with the dextro-rotary form of 3-keto-l7-formyl- A -androstatriene provide for the acyl derivatives of natural cortisone.

While as aforedescribed the 16-halo-l7-hydroxy-l7- (acyloxyacetyl) cyclopentano 10,13 dimethyl- A -decahydrophenanthren-3-one compound (Compound VII) was employed to prepare the 9-halo-ll-hydroxy addition product (Compound VIII) it has been found that it (i. e. Compound VII) upon dehalogenating provides for a 17-hydroxy-17-(acyloxyacetyl)-cyclopentano 10,13 dimethyl A -decahydrophenanthren- 3-one which compound upon reacting with a hypohalous acid produces a 9-halo-ll-hydroxy addition product which addition product upon dehalogenating yields a 11,17 dihydroxy l7 (acyloxyacetyl) cyclopentano- 10,13 dimethyl A dodecahydrophenanthren 3 one. This sequence of steps is outlined schematically as follows, R and x having the same significance as aforedescribed.

p :aIogen 50H .1) m 1 l oH XIV

As illustrative these steps proceeding from Compound (fHsOR o=o I H0 HO XIII VII to Compounds XII and X111 and finally .to Compound XIV is the following:

Example'.X 7 To a suitable reaction vessel containing lolparts by weight of Raney nickel, approximately 100' parts by weight of acetone and about 10 parts by weight of 'water' is added and'intimately mixed?) partsby weight of dl 3,20 diketo 16B bromo -17.- hydroxy 21- acetyloxy-A -pregnadiene and the mixture so obtainedv refluxed in an atmosphere of nitrogen for about 4 hours. The reaction mix is then filtered and the residue washed with warm acetone. The washings and original filtrate are combined and subjected to vacuum distillation. The

residue is then taken up with chloroform and the solution so formed Washed with water and dried. The dried solution is then subjected to vacuum distillation whereupon there is obtained white crystalline dl-3,20-diketo-l7a-hydroxy-Zl-acetyloxy-fi- -pregnadiene.

Similarly the individual optically active isomers such as the natural modification of 3,20-diketo-l7a-hydroxy- 2l-acetyloxy-A -pregnadiene are obtained beginning with the appropriate optically active isomer of 3,20-"

diketo 16 3 bromo 17a hydroxy 21 acetyloxy- A -preg nadiene. The natural modification or dextrorotatory form of 3,20-diketo-l7a-hydroxy-2l-acetyloxy- A -pregnadiene possesses a melting point of 233- 236 C.

The aforedescribed dl 3,20 diketo 17a hydroxy- 21 acetyloxy A -pregnadiene upon reacting with a hypohalous acid such as hypobromous acid in accordance with the process of Example VII produces white crystalline dl 3,20- diketo 9oz bromo 1l 8,17a-dihydroxy- 2l-acetyloxy-A -pregnene which 9-bromo-ll-hydroxy ad dition product upon dehalogenating using Raney nickel provides for dl-3,20-diketo-l1,8,17a-dihydroxy-2l-acetyloxy-M-pregnene which compound has the same infrared spectrum as the (21-) acetate of l7-hydroxy corticoster one. Similarly but beginning with the natural modification of 3,20-diketo-17a-hydroxy-21-acetyloxy-A -pregnadiene the acetate obtained is identical with the (21-) acetate of 17-hydroxy corticosterone.

The natural modification of S-keto-16,17-oxido-17-formyl-A -androstadiene referred to in column 4, lines 311T. is a white crystalline substance melting at l93197 C. The natural modification of 3-keto-l6,17-oxido-l7-carboxy-A -androstadiene referred to in column 4, lines ft. is a white crystalline substance melting at 2l12l2 C. The natural modification of 3,20-diketo-16,17-oxido- 21-diazo-A -pregnadiene referred to in column 5,

lines 52fi., is a yellow crystalline substance melting at l65-168 C. The natural modification of 3,20-diketo- 16/3-bromo-l7a-hydroxy-2l-acetyloxy-M -pregnadiene referred to in column 6, lines 51th, is a white crystalline substance melting at l46l48 C.

This application is a division of co-pending application understood that variations and modifications thereof obvious to those skilled in the art may be made without departing from the spirit or scope of this invention.

'What-ris claimed is:

1.. 1.6 halo 17 hydroxy 17 (acyloxyacetyl) cyclopentano 10,13 dimethyl AN decahydrophenanthren-Zl-one where R is an acyl radicallobtained from a hydrocarbon monocarboxylic acid.

2. The compound 'of claim 1 where the l6-halogen substituent is bromine and where R is an acyl radical obtaincdfrom a fatty acid containing 2 to 4 carbon atoms.

3. 16 halo 17 hydroxy 17- (acyloxyacetyl) cyclopentano 9 halo 11 hydroxy 10,13 dimethyl- A dodecahydrophenanthren-S-one CHQOR l-on Halogen where x is ahalogen atom having an atomic weightgreater than'1-9.00-and where R is an acyl radical obtained from a-hydrocarbon mono-carboxylie acid.

4.-.Thecompound of claim 3 wherein the 16-halogen' substituent and x are bromine atoms and wherev R is an 12 acyl radical. obtainedfrom? a fatty acid containing=,;2 to 4' carbonatoms. 1 .5.. 16- --halo 1:7. -hydroxy -17---(acyloxyacetyl:) cyq droghenanthrena, l'l-dione where x-is a halogenatom having-an atomicweightgreaten' than- 19'.00 and where R an acyl-radical obtained fi-om" aliydrocarbonmono-carboxylic acid.

6. The compound ofclaimfi whereinth'e 16=halogen substituent and x' are bromine atoms andwhere R is an acyl radical-'obtaincd'from a fatty-acid containing 2to"4" carbonatoms.

21-acetyloxy-A-pregnene'.

9. 3,-20 diketo- 911,166 dibromo 1 1 ,1701 dihydroxy-Zl-acetyloxy-A -pregnene.

21"-acetyloxy-A '-pregnene-.

References -Cited inth'e file of tliispat'env UNITED STATES PATENTS" dibromo- 1 1,17 dihydroxy Farrar -a -Aug. 21, 1 9.56;- 

1. 16 - HALO - 17 - HYDROXY - 17 - (ACYLOXYACETYL) - CYCLOPENTANO - 10,13 - DIMETHYL - $4,9(11) - DECAHYDROPHENANTHREN-3-ONE 